title: Mechanism of amyloid β-protein dimerization determined using single-molecule AFM force spectroscopy.
abstract: Aβ42 and Aβ40 are the two primary alloforms of human amyloid β-protein (Aβ). The two additional C-terminal residues of Aβ42 result in elevated neurotoxicity compared with Aβ40, but the molecular mechanism underlying this effect remains unclear. Here, we used single-molecule force microscopy to characterize interpeptide interactions for Aβ42 and Aβ40 and corresponding mutants. We discovered a dramatic difference in the interaction patterns of Aβ42 and Aβ40 monomers within dimers. Although the sequence difference between the two peptides is at the C-termini, the N-terminal segment plays a key role in the peptide interaction in the dimers. This is an unexpected finding as N-terminal was considered as disordered segment with no effect on the Aβ peptide aggregation. These novel properties of Aβ proteins suggests that the stabilization of N-terminal interactions is a switch in redirecting of amyloids form the neurotoxic aggregation pathway, opening a novel avenue for the disease preventions and treatments.
authors.affiliation: Department of Pharmaceutical Sciences, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, NE 68198, United States.
authors.forename: Zhengjian
authors.initials: Z
authors.lastname: Lv
authors.forename: Robin
authors.initials: R
authors.lastname: Roychaudhuri
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Condron
authors.forename: David B
authors.initials: DB
authors.lastname: Teplow
authors.forename: Yuri L
authors.initials: YL
authors.lastname: Lyubchenko
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry*; D006801:Humans; D018625:Microscopy, Atomic Force; D017510:Protein Folding; D055503:Protein Multimerization
chemical_list: D016229:Amyloid beta-Peptides